This invention relates to nanoparticulate, microparticulate, and polymeric film drug delivery systems.
A number of polymeric formulations and polymeric structures have been proposed for a variety of drug delivery vehicles. Both synthetic polymers, which are made by man, and biopolymers, including proteins and polysaccharides, have been proposed for use as carriers for various drugs, including growth factors, genes, and other products of biotechnology. The polymeric vehicle is generally much larger than the drug to be delivered. Some of these polymeric drug delivery vehicles can be broadly categorized as nanoparticles, microparticles, and films. Nanoparticles typically are less than about one micron in diameter and generally range from about 1 to 1,000 nanometers (nm) (1 xcexcm=1,000 nm). Normally, nanoparticles range from about 100 to 300 nm. Microparticles typically have a diameter of above about 1 micron, generally from about 1 to 2,000 xcexcm (2 mm), normally ranging from about 100 to 500 xcexcm. Drug delivery vehicles are also based on polymeric films, which are sometimes used as coatings. These polymeric films are generally from about 0.5 to 5 mm in thickness.
A number of different techniques have been proposed for preparing drug delivery vehicles. The drug can be encapsulated in a polymeric matrix formulation for subsequent sustained release for controlled drug delivery. Some of these techniques are limited by the use of organic solvents that may leave a residue of undesirable organic solvent in the final product. Toxic degradation products have also been found in techniques using synthetic polymers in aqueous solvents.
Drug delivery vehicles in the form of microparticles and nanoparticles are usually formed either by polymer precipitation upon addition of a non-solvent or by gelling the polymer upon addition of a small inorganic ion (salt) and a complexing polymer of an opposite charge. Several of these binary polymeric encapsulation systems, which result from two different polymers, have been described. Given sufficient time, the interior core of the polymer can be completely gelled. The inner core material is usually a polyanionic, or negatively charged, polymer and the particle membrane, or shell, is made from a combination of a polycationic polymer, which is a positively charged polymer, and a polyanionic polymer. The core polymer is usually atomized, or nebulized, into small droplets and collected in a receiving bath of an oppositely charged polymer. However, these systems tend to be characterized by a lack of flexibility in adjusting the physical properties of the particle membrane, which limits the success of these systems.
Multicomponent polymeric microparticles for encapsulation of living cells have been proposed to permit independent modification of mechanical strength and permeability. However, the relatively large size of many of these particles are drawbacks to their use as injectable drug delivery formulations.
Polymeric hydrogels have been proposed for encapsulation of living cells in the production of bioartificial organs. The hydrogel isolates the encapsulated cells from the immune system. For example, immune cells and IgG antibodies can be precluded from entering a cell or tissue implant that is encapsulated by a hydrogel polymeric barrier so that an immunogenic reaction to encapsulated foreign tissue is precluded. However, these hydrogels have a relatively high porosity that is normally suitable only for isolating larger particles. For example, a membrane used to isolate animal pancreatic islet cells can be adjusted to preclude passage of substances of molecular weight from about 70,000 to 150,000 daltons or larger. Thus, although considerable improvements have been achieved in tightening the pore size of hydrogels, generally speaking, the available pore size of hydrogels is typically unsuitable for delivering small drug molecules having a molecular weight of several hundred Daltons in a slow fashion over several days or weeks.
Several methods have been described to further slow down drug release from various polymer formulations. Gel beads can be prepared from complexes of a drug and an oppositely charged water-soluble polymer in a polyelectrolyte. The drug is released by dissociation of the drug-bead complex as the drug is exchanged with counterions present in the surrounding fluid. The release rate is constant, which means the surface area of the drug carrier is constant. Fast release rates for nanoparticles having a high ratio of surface area to volume are unacceptable for most therapeutic use.
Enzymatic release within the organism has also been proposed for delivery from macrodevices, including from drug-chitosan crosslinked beads or gel formulations. These soluble complexes can typically be applied intravenously.
Nevertheless, problems, drawbacks, and limitations persist in developing effective drug delivery systems for some medical applications, including developing injectable formulations of small drugs having site specific application.
The invention described below provides new combinations of multicomponent water-soluble polymers that enable the permeability and release rate of polymeric drug delivery vehicles to be better controlled and to control the release rate of therapeutically relevant drugs. The invention includes methods of making polymeric particles for drug delivery and for other applications in which the drug is covalently conjugated, through a persistent chemical bond or through a dissociable Schiff-base bond, with at least one polymer in a multipolymeric microcapsule, microparticle, nanoparticle, or film to slow its release rate.
For example, the invention includes polymeric complexes in which a gelling polymer and a polymer for permeability control, normally charged polymers of opposite charge, are used to slow the diffusion rate of cationically charged drugs from conjugates of these small molecule drugs with polymers. In a specific embodiment, a dissociable Schiff-base covalent conjugate is formed between dextran polyaldehyde and a small drug, which can include various proteins, growth factors, antigens, or genes in addition to synthetic or naturally occurring chemicals. Physiological reaction conditions are selected that include a dissociable Schiff-base complex that provides a slow drug release, typically from a charged multipolymeric nanoparticle or microparticle.
In another embodiment, a maleic acid anhydride-PEG polymer is used to form a Schiff-base complex with a small molecule drug. The drug-polymer conjugate is then formulated into a suitable nanoparticulate vehicle for release.
In the formation of the persistent covalent bond, a water-insoluble drug is conjugated to a water-soluble polymer to solubilize the drug. The conjugate of drug and polymer is then incorporated into a drug carrier of the invention, including nanoparticles and microparticles. The entire conjugate of drug and soluble polymer is released from the particles by diffusion or by enzymatic degradation of the delivery vehicle.
The method of the invention includes the steps for preparing the drug and polymer conjugates in multipolymeric nanoparticles, microparticles, and films. In one embodiment of the method, the method includes the steps of: providing a stream of uniformly-sized drops of a charged polymer solution in which the particle size of the drops is submicron or at most only a few microns, collecting these droplets in a stirred reactor provided with a polymeric solution of opposite charge, and reacting the droplets and the solution to form the particles. When the drops of polymer are polyanionic and the receiving polymer solution is cationic, then the particles have a polyanionic core and a shell or corona of a polyanionic/polycationic complex. The periphery of the particle has an excess positive charge. Conversely, drops of a stream of cationic solution can be collected in a polyanionic solution. These particles have polycationic core and shell of a polycationic/polyanionic complex with an excess of negative charge on the particle periphery.
In an alternative embodiment of the method, the charged polymer solutions are mixed together in the ratio of 1/1 to 1/4 and gently stirred for 5 to 10 minutes. Spontaneous formation of particles is observed for many combinations of polymer. In a further aspect of the invention, there is included a method of adjusting the rate of release of a drug or drug-polymer conjugate in situ by incorporating an enzymatically degradable polymer into an otherwise nonbiodegradable formulation. For example, chondroitin sulfate, hyaluronic acid, chitosan or a protein may be incorporated into the formulation to allow for enzymatic degradation of the particle by hyaluronidase, lysozyme, or protease(s), respectively, in bodily sites. Such formulations are of advantage in ocular, intravenous, wound-healing and cancer treatments since ocular fluids and serum contain the enzyme lysozyme and wounds and cancer areas generally contain proteases.
Water insoluble drugs can be made water soluble by application of the invention. The drug and polymer complexes prepared with water soluble polymers typically retain water solubility.